IE880266L - Alkylmelatonins - Google Patents

Abstract

beta -Alkylmelatonins are useful as ovulation inhibitors.

Description

61511 ALKYLMELATONINS This invention relates to indolyl derivatives having valuable pharmacological activity, and processes 5 and intermediates for making such compounds.

Melatonin, represented by the structure below, is named systematically as N-[2-(5-methoxy-3~indolyl)- 15 ethyl] acetamide. Trivial navies for the compound include N-acetyl-5-methoxytryptamine and N-acetyl-O-methyl- serotonin. Melatonin, a pineal gland hormone, has ovulation inhibitory activity. Chu, Wortman and Axelrod, Endocrinology, 75, 238 (1964) inhibited both. 20 the estrous phase of the estrous cycle and ovulation in rats and mice with melatonin. pared. Flaugh et al, J. Med. Cfaem., 22, 63 (1979) prepared S~chloro and 6-fluor©melatonin. These compounds 25 shoved increased ovulation blocking activity. c-Metliyl-6-chloromelatonin was also prepared, but e-methyl substitution was found to have no increased ovulation-blocking activity when compared to melatonin itself. 10 H 3 a CH2-CH2-NH-CO-CH3 Several substituted melatonins have been pre- K -2- Frohn at al., Life Sci., 27, 2043 (1980) prepared N-acetyl 5,6-dimethoxytryptannine and longer alkyl chain N-acyl derivatives. Frohn et al. discuss structure-activity relationships of melatonin analogs, 5 and conclude that only exchange of acetyl for propionyl or butyryl and halogenation at the 6-position are beneficial. All other changes are said to decrease activity, a~Methyl-S-chloromelatonin was stated to be inactive. 10 Beta-alkylmelatonins are not described in the prior art. In view of Frohn' s teaching that c?-methyla~ tion destroys activity p-alkylation would not be expected to produce active ovulation inhibitors.

According to the present invention there are 15 provided compounds of the formula (I): |B a r ' o-Vs N« CH-CHs-NH-CO-R 1 6 II II _/4\ zo f \y v*v Rs r4 a) wherein 25 Rl is H, Ci-C4 alkyl, or Ci-C^ alkoxy; R2 is C1-C4 alkyl; R3 is H; R- is H, haloacetyl, Ci=C5 alkanoyl, benzoyl, or benzoyl substituted with halo or C* -C4 alkyl;' 30 Rs and Rs are individually H or halo; and R7 is £ or Cx-C4 alkyl. -3» The invention also provides pharmaceutical formulations comprising a compound of the above formula together with a pharmaceutical!]/ acceptable carrier or diluent, as well as a pharmaceutical method for inhibiting ovulation in a 5 female mammal or bird comprising administering a compound of formula (1).

Preferred compounds of the invention are those in which R1 is C|-C4 alkyl, R2 is Cj-C* alkyl, R3 and 10 R* are H, Rs and Rs are individually H or halo, and R7 -4~ is Cx-C< alkyl. Especially preferred compounds are those in which R1, R3 „ and R4 are as defined for the preferred compounds and R2 is methyl or ethyl, R5 and R6 are individually H, F, or CI, and R7 is methyl. The 5 most preferred compounds encompassed within this invention are p-methyl~6,7-dichlororaelatonin, g-methyl-6-chloromelatonin, and p-methylmelatonin.

The following definitions refer to the various terms used above and throughout the disclosure. 10 The terra "halo" refers to fluoro, chloro, bromo, and iodo.

The term "C^ -C4 alkyl18 refers to the straight and branched aliphatic radicals of 1-4 carbon atoms including methyl, ethyl, propyl, isopropyl, n-hutyl, 15 isobutyl, sec-butyl, and tart-butyl.

The term "C.-C*. alkoxy" includes the straight and branched aliphatic ether radicals of 1-4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. 20 The term "haloacetyl81 refers to chloroacetyl, bromoacetyl, fluoroacetyl, and iodoacetyl.

The term seCi-Cs alkanoyl" includes formyl, acetyl „ propionyl, butyryl, a -methylpropionyl , valeryl, a -methylbutyryl, p -methylbutyryl, and pivaloyl. Pre-25 ferred C1-C5 alkanoyl groups are acetyl and pivaloyl, and most preferably, acetyl.

The term "benzoyl substituted with halo" defines mono- and di-halo benzoyl groups. Specific mono-halo benzoyl groups are chlorobenzoyl, bromobenzoyl, 30 fluorobensoyl, and iodobenzoyl. Preferably,■ the mono- -5- halo benzoyl group is a 4-halo benzoyl, and the preferred halo substituent is chloro.

The di-halo benzoyl groups included generally are those in which both halo suhstituents are the same, 5 and, preferably, are those in which "the halo substicuents are located in the 2- and 4-positions„ Typical di-halo benzoyl groups include 2,4-dichlorobesizoyl, 2,4-dibromo-benzoyl, 2,4-difluorobensoyl, and 2,4-diiodobenzoyl. The preferred group is 2,4-dichlorobeng;oyl. 10 The term "benzoyl substituted with Cxalkyl" contemplates Ct^C The compounds of this invention may be prepared according to any of several processes employing common reactants and procedures. A typical process for preparing the invention compounds comprises acylating a 20 p-alkyl tryptamine. The p-alkyl tryptamines are prepared from indoles. The overall scheme is shown helot-?. -6- Reaction Scheme I R7O-/X- r2cho w 1. J MELDRUM'S ACID PROLINE ft R7O-™» \ Vy! -Vr H Cu powder pyridine Ci-Cs alcohol 10 15 20 25 30 R7O-/*\ f CH—CHs NzH<>, R 0—f' » 0 :o NH NHs heat R R° H 1) HNO2, acetic acid 2) heat 3) HC1 ,2 base R ✓ R70—* \ R6- ' R iK:h-<:H2 |sh CO R1 base R70~*^ Stalky I) 1 i -*=CH=CH2~NH2 «—COOH i5 i acid heat R-*/\ n6 I -CH-CHa-NHz R H -7~ wherein all R2, R5, Rs, and R7 have their previous meaning and X is an activated form of a carboxylic acid of the formula RxC02H, in which R1 is as defined above.

In the above procedure, a 5-alkoxy indole, 5 permissibly mono or dihalogenated at C-6 and/or C-7, is reacted with a Ci~C4 alkylaldehyde (R2CH0) and Meldrum's acid (2,2~diraethyl~4,6-'dio3to-l,3-dioxane) in the presence of proline to yield adduct I. The adduct is decomposed by reaction with copper powder and pyridine 10 in a lower alcohol to yield the corresponding ester of a 0-alkyl indole propionic acid.

The ester can be reacted with hydrazine to provide the hydrazide, which is converted to an aside with nitrous acid. The aside is decomposed under 15 Curtius eonditions to yield a lactam (l-oxo-4-alkyl 6-alkoxy-7,8-permissibly mono or di-halogenated-9H-1,2,3,4-tetrahydropyrido[3,4-b]indole). The lactam ring is opened by reaction with a base to yield the amino acid, a 2-alky1-2-(2-carboxy-3-indolyl)ethyl-20 amine. Decarboxylation of the latter yields the 2- alkyl-2-(3~indolyl) ethyl amine, acylation of which with an activated form of a carboxylic acid of the formula R'COoH, where R1 is as defined above, yields a p-alkyl-melatonin of the invention. 25 Suitable activated forms of a cartooxylie acid of the formula RxCOoH include, for example, the anhydride or mixed anhydride of the carboxylic acid such as acetic anhydride. Acylation can also be accom- -8- plished by reacting the carboxylic acid in the form of its acid halide, such as acetyl chloride, propanoyl bromide and formyl fluoride,, its lower alkyl chloroformate, such as methyl chloroformate and ethyl 5 chloroformate, or its ester, such as methyl formate and ethyl propionate, with the 2-alkyl-2 - {3 ~ indolyl) ethyl amine in the presence of a hydrogen halide acceptor. Hydrogen halide acceptors which can he used include tertiary amines, such as pyridine and tri-10 ethyl amine, alkylene oxides, such as propylene oxide, urea and substituted ureas, such as N-methylurea, and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate and sodium bisulfite. 15 The acylation reaction is preferably conducted in a suitable inert solvent, for example, an aromatic solvent such as "benzene and toluene. The reaction is substantially complete after about one hour to about 48 hours when conducted at a temperature in the 20 range of from about 0°C to about /5°G, more preferably from about 20°C to about 40°C.

An alternative process for preparing the p-alkyl melatonins of this invention, particularly useful for preparing the S and/or /-halo derivatives, 25 involves cyclization of a phenyl hydrazone derivative according to the following scheme. -9- Reaction Scheme II 10 /\ i ft.

In the above procedure, a phenol is nitrated para to the hydroxy group to yield a 4-nitxophenol. The 4-nitrophenol is methylated to yield a 4-aitro alkoxy-benzene, reduction of which yields the 4-amino deriva-30 tive. A diasoniiMa fluoroborate salt, prepared, from the 10- amine by standard procedures, is reacted with 3-acetyl-2-piperidone to yield a phenyl hydrasone. Heating the hydrasone with formic acid yields a l-oxo-S-methoxy~ l,2,3,4-tetrahydro~9H-pyrido[3,4-b]indole. The indole 5 is reacted to the final product melatonin by the same sequence of reactions disclosed in Reaction Scheme I.

It will be noted that the above synthetic method yields halogenated melatonins of unambiguous structure since the preparation of the diazonium salt 10 does not result in the production of mixtures. In addition, the intermediate used to react with the diazonium salt, a 5-alkyl-3-acetyl-2-piperidone, is a known compound which can be prepared by procedures previously disclosed in Ploner et al. Cham Ber, 100, 15 1675 (1967).

This invention also provides compounds where various substituents are attached to the 1-position nitrogen atom. Compounds of this invention in which R4 is not hydrogen are prepared from the p-alkyl melatonin 20 final products of Reaction Scheme I. They are prepared by treating the latter with an appropriate acylating agent. Typically, the side-chain M-acylated compound is reacted with at least an ecruimolar amount of an acyl halide of the formula R*X, in which R4 represents any 25 of the groups defined above other than hydrogen and X is CI, Br and I. . The reaction is carried out in an inert solvent and in the presence of a moderate molar excess (about 10%) of a strong base, such as sodium hydride, at a temperature in the range of 30 from about 10°C to about 50°C for a time sufficient to accomplish conversion. -11- The p-alkyl melatonins of this invention have an asymmetric center, namely, the carbon atom carrying the alkyl group beta to the amide nitrogen atom. Thus the compounds of this invention exist as two enantio-morphs forming a racesiate- This invention includes all such raceme,tes and enantiomers.

The individual stereoisomers constituting the racemates can be prepared in optically active form by resolving the racemic 2-alkyl~2-(3-indolyl )ethylamine. This resolution can be accomplished by amide formation with an optically active acid, separation of the two diastereoisomeric fonts, and hydrolysis of the amide group to yield separated d and 1 primary amines, which can each be converted to a melatonin or a melatonin analogue by reaction with (R1CO)oO or an equivalent acylating agent. The preferred resolving agent is Mosher's acid, Alternatively, an optically active diterpene such as A-menthol or pulegone can be used to prepare enantiomorphs of p-methylmelatonins (R2 is methyl). In this method £-menthol or pulegone is converted, according to Reaction Scheme III below, to an optically active 5-methyl-3-etho3cycarbonyl-2~piperidone which is reacted in a similar manner as the 5-alkyl-3-acetyl-2-piperidone compound of Reaction Scheme II to form the same (but optically active) phenyl hydrazone intermediate. -12- Reaction. Scheme III 10 15 20 25 30 Ha * /i\ #6 3# *3 w m K / puIegon© Ha Pd/C CHs I /?\ • a 2® | | *5 a,*—OH. \^7 A CHa ▼ • /i\ •a s* *.s a*-0H Na/ CrOa H2SO4 GH^ CHs CHa i-rasritho I ? Ha E+ONa (EtO)sCG pnase Transfer cats Ivst EtONa oxalyl chloride (EtO-CO)s CHs I ? 00 1 CHs I CHs I CH-CHs CHs I COOH (Et0-C0)2 , EtONa '' EtOH CaHsCHsOH' CH I Analysis calc. for C17HlsHOs Theory: C, 64.34? H, 6.04,- N, 4.41 Found : C, 64.21; H, 6.14; N, 4.22. 25 A stream of nitrogen was passed through a mixture of 39 ml of ethanol and 110 ml of pyridine for several minutes to remove dissolved air. To this mixture was added 38.5 g (0-12 .mole) of the above adduct 30 followed by 0.76 g of copper dust. The Mixture was -14- refluxed under nitrogen for 16 hours. After cooling, the mixture was filtered through "Hyflo Super Cel". The solvents «ere immediately evaporcited from the filtrate. The residual oil was dissolved in diethyl ether and the 5 ethereal solution was washed with IN EC1 followed by a wash with 20% aqueous ammonium chloride. The organic layer was dried over anhydrous Ha^SO^ » The crude product obtained upon evaporation of the diethyl ether was chromatographed over silica, gel using 3% MeOH in 10 GHCl^. The purified product, 23.3 g of an amber oil, was identified as 3-(5~methoxy-lH-indol-3-yl)pentanoic acid ethyl ester (74% yield).

Analysis calc. for ClsHXsN03 15 Theory? C, 68.94; H, 7.33; N, 5.36 Found : C, 69.18; H, 7.36; N, 5.27.

A mixture of 22.3 g (0.086 mole) of the above ester and 16.6 ml of hydrazine hydrate was re fluxed 20 under nitrogen. After 3% hoars, excess hydrazine hydrate was removed under vacuum. 2-Methyl-2-(5-metho3sy-3-indolyl)propionhydra2;ide crystallised on standing. The filter cake was washed with ether; yield = 16.5 g (78% yield) of colorless hydrazide. A 25 sample melted at 117°C after recrystallization from ethyl acetate.

Analysis calc. for Ct3Hx7M302 Theory: C, 63.14; H, 6.93; N, 16.99 30 Found : C, 62.96; H, 6.66; N, 17.15. -15- A mixrure of 16.5 g (0.067 mole) of the above hvdraside, 100 ml of acetic acide, 200 ml of water and 200 g of ice was swirled while a solution of 6.21 g (0.09 mole) of sodi'oia nitrite in 11 ml of water was 5 gradually added. The resulting acyl azide was immediately extracted into cold diethyl ether. The extract was kept cold as it was washed with aqueous NaHCOg followed by a brine wash. The solution was dried over Na?SOA. The ether was evaporated in vacuo. The 10 residual acyl azide was taken up in 200 ml of cold toluene. This solution was then added slowly to an additional 200 ml of toluene which was being mechanically stirred under nitrogen in an oil bath at 83°C. After the toluene addition stirring was continued for 15 15 minutes. The reaction mixture was allowed to cool to about 50°. A stream of dry HC1 gas was passed into the solution for a few seconds. The mixture was then concentrated to one-half its volume and the resulting insoluble product was collected by filtration. The 20 filter cake was washed with diethyl ether and dried to provide S.79 g (38% yield) of l-oxo-4-methyl-6-methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; m.p. 220°c.

Analysis calc. for C^E^NgO* 25 Theory; C, 67.81; H, 6.13; N, 12.17 Found : C, 67.54; H, 5.97; I, 12.37 -17- over Ha^SO^ and the solvent, evaporated. Chromatography of the crude product over silica gel using ethyl acetate as eluent afforded 2.54 g (85% yield) of pure 3-methyl-melatonin as a colorless glass. 5 Analysis calc. for Ci4Hi8B'2 02 Theory: C, 68.27; H, 7.37; N, 11.37 Found : C, 68-07; H, 7.SO; N, 11.17 10 Example 2 Preparation of p-Ethylmelatonin Following the procedure of Example 1, 5-15 methoxyindole, propionaldehyde, and Me 1 drum8 s acid were condensed. Because the reaction was somewhat more sluggish, a 50% 'excess of propionaldehyde was used and the reaction was allowed to proceed overnight. The yield of adduct,, a pale yellow semi-solid, was 20 quantitative.

Analysis calc. for C18H2iNOs Theory: C, 65.24; H, 6.59; N, 4.23 Found : C, 65.46; E, 6.58; N, 3.99. 25 Following the procedure of Example 1, the adduct was solvolyzed with ethanol in the presence of pyridine and copper dust. Decarboxylation was somewhat less facile than in the previous case. Thus, after the 30 mixture had been refluxed for 19 hours, it was necessary -16- A suspension of 5.79 g (0.025 mole) of the above tetrahydropyridoindole in a solution consisting of 85 ml of ethanol, 60 ml of water, and 8.5 g of KOH was refluxed under nitrogen for 24 hours. After cool-5 ing, the ethanol was evaporated under vacuum. The remaining aqueous solution was chilled to about 0°C as the solution pH was lowered to 6.0 using IN hydrochloric acid. The precipitated amino acid was collected and dried under vacuum, without heat. The yield of crude 10 product 5-methoxy-3~(l-amino»2-propyl)indole»2»carbo3cylic acid was essentially quantitative.

The above crude amino acid was immediately decarboxylated by refluxing in 150 ml of 5 methane-sulfonic acid under nitrogen for 47 minutes. After 15 cooling, the solution was made basic by the addition of 5 M aqueous NaOH. The decarboxylated product was extracted into ether. The ether extracts were dried over Na2S0A. Evaporation of the ether gave 3.92 g of crude tryptamine as a gummy solid. Washing the crude 20 material with a small amount of cold toluene gave 2.48 g of crystalline product (48% yield) comprising purified 5~methoxy~3-(l-amino-2 -propyl) indole.

A solution of 2.48 g (0.012 mole) of the above tryptamine in 18 ml of toluene and 4.5 ml of pyridine 25 was treated with 2.5 ml of acetic anhydride. The mixture was stirred for four hours. The solvents were removed under vacuum, The resulting residue was taken up in CH2C12 and the mixture stirred for several hours with aqueous NaHC03 in order to decompose residual 30 acetic anhydride. The CH^Cl^ solution was then dried -I8~ to complete the reaction by boiling off the excess ethanol and then refluxing at 115°C for another 5\ hours. The yield of ester --•3-(5-methoxy-lH-indol»3-yl )perrfcan.oic acid ethyl ester — after silica gel 5 chromatography, using 2% EtQAc in toluene as the eluant, was 60%.

Analysis calc. for C1SH2^N03 Theory; C, 69.79; H, 7.59; N, 5.09 10 Found : C, 69.53; H, 7.40; N, 5.01.

The above-prepared ester was re fluxed in hydrazine hydrate as previously described. Complete reaction required 6^ hours. The yield of 2-ethyl-2-15 (5-metb.oxy-3-indolyl )propionhydrazide, after recrystal-ligation fro® ethyl acetate, was 45%; m.p. 101-103°C.

Analysis calc. for C14HiSM3Q2 Theory.- C, 64.35; H, 7.33; N, 16.08 20 Found : C, 64.20? E, 7.53; N, 15.88 The corresponding hydrazide was converted to acyl azide, and the azide thermally rearranged, and cyclised, to the lactam l-oxo-4-ethyl-6-methoxy-l,2,3,4-25 tetrahydro«9H«pyrido[3,4-fa]indole according to the procedure of Example 1. Instead of allowing the final product to crystallize from the concentrated reaction mixture, the toluene was completely evaporated affording a residue comprising crude lactam; yield = 75%. A sample 30 of the lactam was recrystallized from acetone/water for analysis. -19™ Analysis calc. for C14H16N2Q2 Theory: C, 68.83; H, 6.60; N, 11.47 Found : C, 68.68; H, 6.74; N, 11.37 5 Hydrolysis of the lactam was carried out as previously described in Example 1. The yield of crude 2-carboxy-3-(l-amino-2-butyl)-5-methoxyindo1e was 96%. As before, it was decarboxylated without further purification (the only change from the procedure in 10 Example 1 being that 3M methanesulfonic acid was employed). Several hours were required for complete reaction. The yield of the tryptamine, 3-(l~amino-2-butyl)-5-methoxyindole, was 36%. The crude product, an oil, was acetylated directly without further purifi-15 cation in the manner described in Example 1 for the 0-methyl compound, The product, p-ethyl melatonin thus prepared, after silica gel chromatography, was a colorless glass. 20 Analysis calc. for CiSHoo^202 Theory: C, 69.20; H, 7.74; N, 10.76 Found : CP 69.25; H, 7.99; N, 10.59 Example 3 25 preparation of p -Me thy 1 - 6 - chl orome1atonin Following the procedure of Example 1, a solution of 10.0 g CO.055 mole) of 5~me thoxy-6-chl oiro indo 1 e, 30 3.1 ml (2.44 g{ 0.055 mole) of acetaldehyde, and 7.94 d -20- (0.055 mole) of Meldrum's acid in 90 ml of acetonitrile was stirred for 48 hours. The solvent was removed under vacuum, and the adduct thus prepared was recrystallised by dissolving in wain toluene and immediately cooling. 5 The adduct was obtained as slightly pink crystals? ra.p. = 145°C; yield = 16.5 g (85%). The elemental analysis of the product showed a slightly elevated percentage of carbon. However, the NMR spectrum indicated that the product was pure and had the indicated 10 structure.

Analysis calc. for Cj7H18N0SC1 Theory: C, 58.04; H, 5.16; N, 3.98; CI, 10.08 Found : C, 59.34; H, 5.15; N, 3.84; CI, 9.69 15 The solvolysis and decarboxylation of the adduct (11.0 g; 31.3 muoles) using ethanol, pyridine, and copper dust was carried out by the procedure of Example 1. The yield of 3-(5-methoxy«-6-chloro-lH« 20 indol-3-yl)pentanoic acid ethyl ester, a pale yellow oil, after chromatography over silica gel using 10% EtOAc/90% toluene was 8.68 g (94%).

Analysis calc. for CxsHj8N03C1 25 Theory: C, 60.91; H, 6.13; N, 4.74; CI, 11.99 Found : C( 60.67; H, 5.86; N, 4.93; Cl, 11.73 30 A mixture of 8.68 g (29.3 mmoles) of the above ethyl ester and 6 ml of hydrazine hydrate was heated at 140°C under nitrogen in a flask fitted with an air 10 -21- cooled condensor. After 6^ hours, the excess hydrazine hydrate was removed under vacuum. The 2-raethyl~2-(5~ methoxy-*5-chloro-3-indolyl)-propionhydrazide thus prepared was recrystallized from ethyl acetate; Yield = 7.13 g (86%); in.p. = 154-155°C.

Analysis calc. for Ci3HiSM302Cl Theory: C, 55.42; H, 5.72; N, 14.91; CI, 12.58 Found : C, 55.14; H, 5.51; N, 14.49; Cl, 12.78 The above hydrazide (7.13 g, 25 nimoles) was converted to the corresponding acyl azide, the azide thermolyzed and rearranged at 80° in toluene, and the rearranged product cyclized with HC1 according to the 15 procedure of Example 1. The yield of crude, light tan, lactam, l-oxo-4~methyl-6-netho3ey-7«chloro-l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, product, (sa.p. = 249~252°C) was 4. 77 g (72%). 20 Analysis calc. for C13H13H202CX Theory: C, 58.99; E, 4.95; N„ 10.58 Found : C, 59.45; H, 4.77; N, 10.72 The crude lactam (4.77 g, 18 mmoles) was 25 hydrolyzed with aqueous ethanolic KOH as described in Example 1. The yield of crude amino acid, 2-carboxy~3-(l«-amino-2-propyl)-5-jBethosy'-6'-chloroindoleI, was 3.98 g (78%). The crude product (3.0 g; 10.6 mmoles) was decarboxy1 ated, using the procedure of Example 1, by 30 reflusting in 100 ml of 3M HC1 overnight. The acidic -22- solution, was decolorized with activated carbon and was then basified with 5M NaOH. The amine was extracted into diethyl ether. After drying the ether extract over Na^SO^, the diethyl ether was removed in vacuo leaving 5 as a residue the crystallized tryptamine, 3-(l-amino-2~ propyl)-5-methoxy~6«cb,loroin.d,ole; m.p. 133~4°C. The yield, after recrystallisation from toluene/hexsne„ was 1.52 g (64%). 10 Analysis calc. for CaoHa5H2OCl Theory: C, 60.38; H, 6.33; N, 11.74; Cl, 14.85 Found : C, 60.11; H, 6.05; N, 11.93; Cl, 15.06 A solution of 1.51 g (6.3 mmoles) of the above 15 tryptamine in 10 ml of toluene and 2.5 ml of pyridine was treated with 1.5 ml of acetic anhydride. After allowing the reaction mixture to stand for three hours at room temperature, the volatile materials were removed under vacuum. The residue was dissolved in ethyl 20 acetate, and washed with aqueous HaHC03, and brine. The ethyl acetate solution was dried over Ma^SO^, and the solvent removed by evaporation. The residual oil was crystallized from toluene/hexane yielding 6-chloro-0~ methylmelatonin, (m.p. - 133~5°C; 1.09 g, 51%). 25 Analysis calc. for Ci4HX7N202C1 Theory: C, 59.89; H, 6.10; N, 9.98; Cl, 12.63 Found : C, 50.03; H, 6.22; N, 9.75; Cl, 12.92 -23- Example 4 Preparation of p-methyl-6,7-dichloromelatonin 5 To a chilled solution (below 0°C) of 13.2 ml of freshly distilled boron trifluoride etherate in 125 ml of methylene chloride, in a 1 liter 3-neck round bottom flask equipped with nitrogen inlet tube and stirrer, were added 13.7 g of 4-amino«2,3-dichloroanisole . 10 and 65 ml of methylene chloride. The addition was made over a 20 minute period with vigorous stirring. Next, a solution of 10.6 ml of t-butyl nitrite and 65 ml of methylene chloride was added dropwise over a 30 minute period to the reaction mixture. After the addition had 15 been completed the reaction mixture was kept below about 0°C, with stirring, for about 40 minutes. Then 375 ml of pentane ^ere added to desoluhilise the 2,3-diehloro-4-methoxybensenediasonium fluoroborate formed in the above reaction. The diluted reaction mixture was 20 stirred for an additional hour, then filtered. The filter cake, comprising the diazonium salt, was dried in vacuo to yield a white powder melting at 153~154°C with decomposition. 25 To a solution of 2.81 g (9.67 mmoles) of 2,3~dichloro»4-raethoj£yheBzenediasoD.iua fluoroborate in 38 ml of u£ter and 46 ml of acetic acid were added 1.50 g (9.67 mmoles) of 3 - acetyl-5 -methyl «2 ~;o iper idone. Within about 1" minute 3-[2-(2,3-dichloro~4Htaethoxy)~ 30 phenyl hydrasono]~5~methyl-2-piperidone commenced to -24- separate. After stirring for 20 minutes 21 ml of water were added. Stirring was continued for another hour. The reaction mixture was then chilled for several hours and 3-(substituted phenylhydrarcorxo)-5-methyl~2-piperidone 5 was collected by filtration; m.p. 211-214°C; Yield = 2.87 g (94%).

Analysis calc. for Ct3HtsN302Cl2 Theory: C, 49.38; H, 4.78; N, 13.29 10 Found *. C, 49.56; H, 4.90; N, 13.20 A mixture of 2.87 g (9.08 mmoles) of the hydrazonopiperidone and 90 ml of 85% formic acid was heated at about 100°C for one hour. The hot solution 15 was diluted, slowly with 18 ml of water at which point the l-oxo~4-methyl-6~methoxy-7,8-dichloro-l ,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole formed in the reaction commenced to separate. After chilling the reaction mixture for several hours the product was collected by 20 filtration and recrystallized from ethanol. The yield of colorless, crystalline product was 1.85 g (68%).

Analysis calc. for C13Hi2N202Cl2 Theory: C, 52.19; H, 4.04; N, 9.36 25 Found : C, 52.32; K, 4.15; N, 9.19 Following the procedure of Example 2, 1.85 g (6.18 mmoles) of l-oxo-4-methyl-6-methoxy-7,8-dichloro-1 p 2,3,4-tetrahydro~9H-pyrido [3,4~b]indole were hydro-30 lyzed with aqueous alcoholic KOH. The yield of crude -25- exaino acid, 2~carhoj£y-3~(l-amino-2~propyl)-5-methoxy-6,7-dichloroindole, thus formed was quantitative. The amino acid was decarboxylated without further purification, using the procedure of Example 2, with 3M hydro-5 chloric acid for 48 hours to yield 3-(l-amino-2-propyl)™ 5-methoxy-6, 7 - di chloroindo1e.

The hydrolysis solution was cooled, then made basic by the addition of IN MaOH. After chilling the solution the product was collected by filtration, then 10 dried. The filter cake was washed with cold CH^Cl^. The 3- (l-amino-2-propyl )-5-methoxy-6,7 - di chl or o i ndo 1 e thus prepared was a slightly tan solid weighing 1.05 g (62% yield). 15 Analysis calc. for C12H14N20C12 Theory: C, 52.76; H, 5.17; N, 10.26 Found; C, 52.52; H, 5.36; N, 9.97 The acetylation of 1.05 g (3.84 mmoles) of the 20 tryptamine with acetic anhydride was carried out as described in Example 2. The p-methyl-6,7-dichloro melatonin thus prepared was purified by digesting in ether. The yield of colorless product was 0.80 g (66%). 25 Analysis calc. for Ci4Hi6N202C12 Theory: C, 53.35; H, 5.12; N, 8.89; Cl, 22.50 Found : C, 53.09; H, 5.15; N, 9.06; Cl, 22.51 -26- Example 5 Preparation of R-(-) and S-(h-) 3~ethoxy~ carbonyl-5-methyl-2-piperidone.

A mixture of 156 g (1 mole) of (£)-menthol and 1032 g of 35% sulfuric acid was stirred mechanically while a solution of 220 g (2.2 moles) of chromium trioxide in 1032 g of 35% sulfuric acid was added at a rate such -that the reaction temperature did not exceed 30eG. Stirring was continued at 30°C for 3% hours. The reaction mixture was extracted repeatedly with diethyl ether. The ether extracts were combined, concentrated, and then extracted with 1M aqueous NaOH. The aqueous extract was acidified with 12N hydrochloric acid and then extracted several times with diethyl ether. The ether extracts were combined, washed with brine and dried over Na2S0A. After evaporating the diethyl ether, the residue, comprising S-(H-)~3,7-dimethyl»6-oxooctanoic acid formed by the above oxidation, was distilled. The yield of redistilled ketoacid, bp [6.65 Pa (0.05 mm Hg) ] = 104°C, was 74 g (40%). [a-]25 = + 7.8° (c = 10, MeOH).

Analysis calc. for C3 oH* 8^3 Theory: C, 64.49; H, 9.74 Found s C, 64.41,- Hf 9.48 -27- A solution of peroxytrifluoroacetic acid, prepared by slow addition of 16.4 ml (0.60 mole) of 90% hydrogen peroxide to a mixture of 100 ml (149 g, 0.71 mole) of trifluoroacetic anhydride and 100 ml of methyl-5 ene chloride, was slowly added to a mixture of 74 g (0.40 mole) of S- ( h-)~3 ,7-dimetliyl-S-oxooctanoic acid, 400 ml of methylene chloride, and 102 g (0.72 mole) of disodium hydrogen phosphate. This reaction mixture was stirred for 48 hours at room temperature (24°C) and then 10 washed thoroughly, first with water, then brine. After drying over Na,S0A the solvent was evaporated and the residual liquid was distilled affording 64.2 g (79% yield) of S~(-t*)~3-methyl-5-isopropoxycarbonylpentanoic acid, bp [6-65 Pa (0.05 mmHg)] = 101-107°C. [a]25 = + 6.4° (c = 15 10, MeOH).

Analysis calc. for CtoHx804 Theory: C, 59.39; H, 8.97 Found : C, 59.23,- H, 8.69 20 A solution of 50 g (0.25 mole) of the above isopropyl ester in 250 ml of anhydrous 2M ethanolic sodium ethoxide was stirred at 40°C for three hours. The cooled solution was poured into a mixture of ice and 25 excess 2M hydrochloric acid then extracted with diethyl ether. The ether extract was washed with brine, then dried. The ether was evaporated and the liquid residue distilled. The yield of S-( + )~3~mefchyl-5~e"fchoxycarbonyl -28- pentanoic acid, bp [3.39 Pa (0.03 mm Hg)] = 100°C, was 33.2 g (71%). [a]2s = 4-6.6° (c * 10, FieOH).

Analysis calc. for C^HiS04 5 Theory: C, 57.43; H, S.57 Found *. C, 57.46; H, 8.28 Sodium ethoxide was prepared in a 500 ml, three-necked, flask by dissolving 13.1 g (0.57 g-atoms) 10 of sodium in 100 ml of absolute ethanol. Most of the excess ethanol was removed under vacuum. Then 260 ml of ethyl carbonate and 9.0 g of "Adogen 464" (a phase transfer catalyst) were added. The flask was fitted with a mechanical stirrer, a 250 sal dropping funnel 15 (without pressure equalising side arm), and a jacketed 21 cm Widmer column. Heating the flask in an oil bath at 160°C caused the balance of the ethanol to distill off and brought the ethyl carbonate to the point where it distilled very slowly through the widmer column. 20 While heating at 160°C 26.8 g (0.14 mole) of S-(+)-3- methyl-5-ethojcycarbonyXpentanoic acid in 100 ml of ethyl carbonate were added over a one hour period. After an additional hour of heating, ethanol distillation had ceased, and the temperature of the distilling ethyl 25 carbonate had reached 125-6°C. The mixture was cooled and the sodium salt of S- (+)-3~iaethyl-5-bis (ethoxy-carbonyl )pentanoic acid was collected and quickly washed with a small amount of THF. The salt was then added to a mixture of ice and excess 2H HC1, then extracted into 30 diethyl ether. The ether extract was washed with brine -29- and dried over Na^SO^. The diethyl ether was evaporated and the residue subjected to HFLC chromatography over a Waters "Prep 500" silica gel column using methylene chloride followed by 1% methanol in methylene chloride 5 as the eluant. Fractions containing s-(+)-3~methyl-5™ bis(ethoxycarbonyl)pentanoic acid as determined by TLC were pooled and the solvent recovered from the pooled fractions to yield S-{*)»3-methyl-5-bis(ethoxycarbonyl)-pentanoic acid. 10 A solution of 4.31 g (IS.6 mmoles) of $-(+)- 3-methyl-5~bis(etboxyearbonyl)pentanoic acid in 50 ml of ethanol was treated with one equivalent of ethanolic sodium ethoxide. The ethanol was removed in vacuo and the residual salt thoroughly dried. This salt was 15 suspended in cold benzene and treated with 1.44 ml (2.10 g, 16.5 iraaoles) of oxalyl chloride. After the initial rapid reaction ceased,, the solution was filtered and the benzene evaporated under vacuum. The acid chloride formed was solubilized in a small amount of 20 acetone and added to a solution of 1.19 g (17 ©moles) of sodium azide in 6 ml of water at a rate such that the temperature was maintained at 10-15°C. After one hour, S~(*)-3-raethyl-5-fois(ethoxycarhonyl)pentanoyl azide was extracted into benzene. The extract was dried over 25 Na9S0^, and the solvent removed under vacuum. The residue was placed in solution with a small amount of dioxane (^>0.5 ml) and added dropwise to 5 ml of benzyl alcohol which had been heated to 140cC. After heating for an additional 30 minutes the excess benzyl alcohol 30 was removed under vacuum, leaving 2.9 g (48% yield) of ~30~ benzyl N-S-(-?-)-. [2~methyl~4~bis(ethoxycarbonyl) ]butyl-carbamate. A small sample of this material was further purified by silica gel chromatography. [a]25 = + 9° (c = 10, MeOH). 5 Analysis calc. for C19H27NOs Theory: C, 62.45; H, 7.45; N, 3.83 Found : C, 62.26; H, 7.51; N, 3.72 10 A solution of the above carbamate (2.7 g, 7.4 mmoles) in 200 ml of ethanol was hydrogenated over 0.5 g of 10% Pd/C. When hydrogen uptake ceased the catalyst was removed by filtration and, the filtrate allowed to stand at room temperature (24°C) for 48 hours. After 15 evaporating the solvent the residual lactam, s-(+)-3~ ethoxycarbonyl-5-methyl-2-piperidone, was crystallized from diethyl ether, affording 1.10 g (80% yield) of crystalline material; m.p. 93-94®. [a]25 - +36.7° (c = 10, MeOH). 20 Analysis calc. for C9H1SN03 Theory: C, 58.35; H, 8.16; N, 7.56 Found : C, 58.23; E, 7.68; N, 7.60 25 R-(-)-3-ethoxycarbonyl~5-methyl-2~piperidone was prepared in similar fashion by reacting a mixture of 156 g (1 mole) of crude (~)-methone and (-f-)-isoHienthone (obtained by hydrogenation of (+)»pulegone over Pd/C), suspended in 687 g of 35% sulfuric acid, with a solution 30 of 146 g (1.46 moles) of chromium trioxi.de in 687 g of -31- 35% sulfuric acid. The chromium trioxide solution was added at a rate such that the reaction temperature did not exceed 30°C. Stirring was continued for another 3^ hours after which the product, R-(-)-3,7-dimethyl-6-oxo~ 5 octanoic acid, was extracted into diethyl ether. The ether extract was concentrated and extracted with 1M aqueous MaOH. The aqueous extract was acidified with 12N hydrochloric acid and then extracted with diethyl ether. The ether extract was washed with brine, then 10 dried over Na9SOA, and the ether removed under vacuum. The residue was distilled affording 74.7 g (40% yield) of R»(~)-3,7»diMethyl~6~oxooctanoic acid, hp [6.65 Pa (0.05 mm Eg)] = 110°C. This product was identical to that obtained by oxidation of (£)-menthol except that it 15 exhibited the opposite sign of rotation.

Carrying the (R) - (-}ketoacid through all the steps described -above for the (S)-(+) isomer afforded the (R)-(~)»3-ethoxycarbonyl"5»methyl-2-piperidone.

This isomer was identical to the (S)-(-f)product in all 20 respects except for the sign of the rotation of plane polarized light.

Exaarole 6 25 Preparation of S- (-)~p-Methylmelatonin and R-( + ) - (J -Methylmelatonin Following the procedure of Example 4, a mixture of 2.50 g (13.5 mmoles) of (R)-(-)-3-ethoxy-30 carbony 1 -5-methyl-2-piperidone and 40 ml of 0.75H NaOH -32- was stirred at room temperature (24°C) for 20 hours, then chilled to 0°C. The pH was lowered to about 3-5 with 3M hydrochloric acid, and 3.00 g (13.5 mmoles) of p-anisyldiazonium tetrafluoroborate (prepared from 5 p-anisole by the procedure set forth in Example 4) were added in small portions- The reaction mixture was chilled to about 0°C overnight. The crude product was collected by filtration, washed with cold water, then dried. Yield of crude hydrazone, R-(-)-3~(p-methoxy-10 phenylhydrazono)-5-methyl-2-p iperi done, m.p- 201°C, was 2.50 g (75% yield). A small sample of hydrazone was further purified by passage over a short silica gel column with ethyl acetate as the eluant; rotation [a]25 = -82° (c = 9.5, MeOH). 15 Analysis calc. for (^31217^302 Theory: C, 63.14; H, 6.92; N, 16.99 Found : C, 62.97; H, 6.80; N, 16.88 20 A mixture of 2.30 g (9.3 mmoles) of hydr azone and 17 ml of 85% formic acid was heated at 85-90°C for three hours. Water was then added dropwise until crystallization commenced. The crystallization mixture was cooled, then chilled overnight- The crude product 25 was collected by filtration, washed with water, then dried. Yield of crude s-(™)-lactam, S-(-) l-oxo-4- methyl-6-methoxy~l ,2,3,4-tetrahydro»9H-pyrido [3,4-b]» indole, (m.p. 215°C) was 1.41 g (86%). A small sample was recrystallized from an acetone/water solvent mix- 30 ture. This product was spectroscopically identical -33- to the racemic material previously described in Example 1; rotation [c]25 = -6° (c=5, MeOH).

Analysis calc. for C13H1 (R)-( + )-p-iaethylmelatonin was synthesized from 15 {S)-{-f-)-3~ethoxycartoonyl~5~oiethyl-2-piperidane as described above. It was spectroscopically identical to the above (S)-(-") material but exhibited the opposite sign of rotation. 20 Example 7 Preparation of S-(-)™£™methyl-6~chloromelatonin and R™(+)-p-methyl-6-chloromelatonin 25 A solution of 4.0 g (21 mmoles) of 3-chloro~4- methoxynitrobenzene in 200 ml of toluene was hydrogenated over 0.4 g of 5% platinum on alumina. The catalyst was removed by filtration and the solvent evaporated from the filtrate. The crude 3-chloroanisidine prepared 30 was placed in solution in diethyl ether and treated with -34- ethereal HCl to produce the hydrochloride salt, which was collected and dried? weight = 2.48 g (61% yield).

A mixture of 2.40 g (12*4 mmoles) of 3-chloroanisidine hydrochloride in 7 ml of 4M HCl was treated, 5 at 0°C, with 0.86 g (12.5 mmoles) of sodiust nitrite in 5 ml of water. After stirring at 0°C for an hour the solution was filtered, and the filtrate added slowly to an ice cold solution of 2.6 g (24 mmoles) of sodium fluoroborate in 8 ml of water. After stirring at 0°C 10 for an hour the salt was collected and washed successively with, cold 5% sodium fluoroborate solution, cold methanol, and ether. The dried 3-chloro-4-methoxybenzene diazonium fluoroborate thus prepared weighed 2.2 g (69% yield). 15 A mixture of 2.03 g (11.0 mmole) of (R)-(-)-3~ ethoxycarbonyl~5-methyl~2~piperidone and 30 ml of 0.75M NaOH was stirred at room temperature (24°C) overnight. The solution was cooled to 0°C and the pH lowered to 3.5 with 3M hydrochloric acid. The diazoniim salt (2.8 g, 20 10.9 mmoles) was added in small portions and the reaction mixture cooled to about 0°C overnight. The product, R- (- )-3- (3-chloro-4-methoxy )phenylhydrazono-5-methyl-2-piperidone, was collected, washed with vater, and dried; weight = 2.30 g (75% yield); m.p. = 205°C. A 25 small sample was further purified by chromatography over a short silica gel column using ethyl acetate as the eluant. [a]25 = -58° (c = 10, MeOH).

Analysis calc. for CagHt3M302C1 30 Theory: C, 55.42; H, 5.72; H, 14.91; Cl, 12.58 Found : C, 55.79; H, 5.78; N, 14.72; Cl, 12.69 -35- A mixture of 2.20 g (7.8 moles) of the R-(-) hydrazone and 20 ml of 90% formic acid was heated at 85° for three hours then slowly diluted with an equal volume of water. The mixture was allowed to cool and then 5 chilled overnight. The dark precipitate was collected, washed with water, then recrvstallized from acetone/water, yielding 1.20 g (60% yield) of 8~(-)-l-oxo-4-methyl-6-methoxy-7-chloro-l ,2,3,4~tetrahydro~9H~pyrido [3,4-b] -indole; m.p. = 248°C. [e]25 = -12.2° (c = 10, MeOH). 10 Analysis calc. for C13Hj3N2 02Cl Theory: C, 58.99; H, 4.95; N, 10.58; Cl, 13.39 Found : C, 59.16; H, 4.88; N, 10.80; Cl, 13.15 15 The conversion of (S)-(~)-lactam to (S )-{-)- 5 - chl or o - p -me thy liae 1 atenia was carried out as described previously in Example 3. The product, S-(~)~p-methyl-6-chloromelatonin, was spectroscopically identical to the racemate, but gave an optical rotation of [a]25 = 20 -13.2° (c = 10, MeOH).

(R)-(H-)-6-chloro-p»methylmelatonin was synthesized from (S)-( + )-3-ethoxycarbonyl-5~methyl-2-piperidone in the same manner as described above. The stereoisomer was identical to the (S)-(-) material except for the 25 sign of rotation.

The compounds of the invention are ovulation inhibitors. The degree of ovulation inhibitory activity was determined according to the following protocol. -36™ Adult female rats with regular estrus cycles of four days each are employed. The estrus cycle consists of 2 days of diestrus followed by a day of proestrus and then, a day of estrus. Daily vaginal smears were recorded, and rats were selected after they had demonstrated, at least two consecutive 4-day estrus cycles. On the afternoon of proestrus, luteinizing hormone (LH) is released into the blood by the pituitary gland. The IS travels to the ovary where it induces ovulation, resulting in the presence of eggs in the oviduct on the day of estrus.

The test compound is administered orally to the non-control rats at noon on the day of proestrus. Both control and non-control rats are sacrificed on the following day (estrus). The oviduct is removed from each rat and examined microscopically for the presence of ova. A 50% decrease in the number of ovulating non-control rats, relative to the number of ovulating control rats, indicates the compound is active in blocking ovulation and establishes the minimum effective dose needed to inhibit ovulation.

Table I below discloses the results obtained when testing some p-methyl melatonins in the above procedure. Melatonin is included in Table I for comparative purposes. Column 1 gives the name of the compound, and column 2 the minimum effective inhibitory dose in sags per kilogram of rat weight. -37- Table I 10 15 20 25 30 35 Name of Compound Melatonin 3-methyl melatonin R-(+)~p-methyl melatonin p -ethyl melatonin, p~methyl-6-chloro» melatonin a- (*) ~p-metb,yl»6» chloromelatonin S-(~)-p-methyl-S-chloromelatonin p-Methyl-6,7-dichloromelatonin Minimum effective inhibitory dose in mg per kilogram of rat weight 32.0 1.0 1.0* 1.0 2.0 1.0 >5.0 15.0 Blocked 40% of non-control rats relative to control rats at this dosage.

The p-alkyl derivatives also have a longer anovulatory effect than the a-methyl derivatives or the mono-halo derivatives of the art. Thus they can be administered one or two hours prior to noon on the day of proestronus and still act as ovulation inhibitors.

As ovulation inhibitors, the compounds of this invention can be used as contraceptive agents in female mammals and birds. Their oral activity renders them particularly useful in achieving contraception, and population control, of unwanted (in their present numbers) mammalian species. For example, the compounds of this -38- invention can be formulated in coxabination with baits and/or attractants and placed in feeding stations accessible to undesirable rodents and other small animals including Canidae such as coyotes, foxes, 5 jackals, and wild dogs; and birds, such as starlings, gulls, redwing blackbirds .■ and pigeons, to greatly reduce the excess population- They can also be used to reduce hazards to aviation by lessening the presence of birds and animals on runways in the vicinity 10 of air fields. They also can be used to reduce the population of undesirable birds and animals so as to aid in the prevention and the spread of disease, and to reduce the destruction of property in both rural and urban areas.

The compounds of this invention, when acsainis-15 tered in an effective amount will inhibit ovulation and therefore conception in birds and mammals. The usual daily dose is from about 0.02 milligrams to about 20 milligrams per kilogram body weight of the recipient. The preferred daily dose is from about 1 milligram to 20 about 8 milligrams per kilogram body weight of the recipient.

The compounds of this invention can be administered as such, or they can be compounded and formulated into pharmaceutical preparations in unit dosage form for 25 oral or parenteral administration- The compositions are preferably formulated in a unit dosage from, each dosage containing from about 5 to about 500 mgt more usually about 25 to about 300 mg, of the active ingredient- In the compounding or formulation, organic or inorganic 30 solids and/or liquids which are pharmaceutically accept -39- able carriers or diluents can be employed. Suitable such carriers will be well recognised by those of ordinary skill in the art. The oral compositions may take the form of tablets, powder granules, capsules, suspen- invention may also be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

The following formulation examples are illustrative only. sions and solutions.

The compositions of the Formulation 1 p-methyl-6-chlorome1atenia starch, dried magnesium stearate 250 200 10 Total 460 mg The above ingredients can be mixed and filled into hard gelatin capsules in 460 rag quantities. -40- Fonmulatiop. Z h tablet can be prepared using the ingredients below: Quantity (mo/tablet) p-methyl-S,7-dichloromelatonin 125 cellulose, microGrvstalline 200 silicon dioxide, fumed 5 stearic acid 2 Total 332 mg The components can be blended and compressed to foxm tablets each weighing 332 mg.

Claims (13)

1. -41- What we claim is: 1. A compound of the formula (I): R2 y \ R70—• * CH-CHs-NH-CO-fl ^VW (D R5 R4 10 wherein R1 is H, Ci-C< alkyl, or Cx-C4 alkoxy; R2 is C1-C4 alkyl; R3 is H; R4 is H, haloacetyl, C,-Cs alkanoyl, benzoyl, 15 or benzoyl substituted with halo or C*-C4 alkyl; Rs and R6 are individually H or halo; and R7 is H or Ci-C< alkyl.

2. A compound as claimed in claim 1 wherein R4 is H, haloacetyl, C^-Cg alkanoyl, benzoyl, or benzoyl 20 substituted with halo or methyl.

3. A compound as claimed in claim 2 wherein R1 is Cj-C4 alkyl; R2 is Ci-C4 alkyl; R3 and R4 are H; 25 R5 and Rs are each individually H or halo; and R7 is Cj-C^ alkyl.

4. A compound as claimed in claim 3 wherein R1 is C3.-C4 alkyl; R2 is methyl or ethyl; 30 R3 and R4 are H; -42- 15 20 25 30 Rs and a3 are each individually E, F or Cl; and R7 is methyl.

5. A compound according to claim 1 of the formula /\ CHaO-f ®" (pHs -*—CH-CHs-NH-CO-CHs ; Cl / A.

6. J 10 namely, p~methyl~6,7~dichloromelatonin. S. a compound according to claim 1 of the formula CHsO--» /\ CHs 4l namely, H-CHs-NH-CO-CHo ; H I-methyl-mslatonin.

7. A compound according to claim 1 of the formula CHsO—• CHs i H-CHs—NH-CO-CHa • m Cl / H namely, p -methy 1 -6-chloroms 1 atonin.

8. A pharmaceutical formulation comprising as an active ingredient a compound of formula (I) as claimed in any one of claims 1 to 7 associated with one or more pharmaceutically acceptable carriers or diluents therefor.

9. A compound of formula (I) as claimed in any one of claims 1 to 7 for use as a pharmaceutical compound. -43-

10. A process for preparing a compound of 5 10 15 20 formula (I) as claimed in any one of claims I to 7 which comprises a) acyl a ting an intermediate amine of the formula so as to provide a compound of formula {I) in which R^ is hydrogen; or b) reacting a compound of formula (I) in which R4 is hydrogen with an acyl halide of the formula R4X, wherein R4 is haloacetyl, Cx-Cs alkanoyl, benzoyl, or benzoyl substituted with halo or Ca~C4 alkyl and X is halo, in the presence of a strong base to produce a compound of formula (I) wherein R4 is other than hydrogen.

11. A compound of formula (I) whenever prepared by a process according to claim 10.

12. A compound of formula (I) substantially as hereinbefore described with reference to any one of the Examples. formula (I) substantially as hereinbefore described with reference to any one of the Examples.

13. A process for preparing a compound of F. R. KELLY & CO AGENT FOR THE APPLICANTS.